Despite dramatic recent advances in identifying peptides important in the regulation of body weight, the mechanism(s) underlying the development of human obesity remain obscure. We hypothesize that a reduce capacity for the oxidation of dietary fat by skeletal muscle plays an important role in the pathogenesis of obesity. In our previous work we have observed that in addition to significant differences between obesity prone and obesity resistant phenotypes, marked gender differences in the oxidation of dietary fat were also present. We have speculated that this, is in part, due to increased skeletal muscle uptake of dietary fat in the female rats. Each specific aim is an extension of our previous work and each are designed to comprehensively examine the role that reduced oxidation of dietary fat plays in the development of obesity. Differences in nutrient preference across gender will also be examined. Studies will be accomplished using a combination of whole animal and in vitro preparations in HFD diet-induced model of obesity model of obesity. In order to accomplish these objectives, we are proposing to use a combination of indirect calorimetry and tracer studies. Collectively the experiments have been designed to examine the interaction of glucose, triglyceride and tracer studies. Collectively the experiments have been designed to examine the interaction of glucose, triglyceride fatty acids and intramuscular triglyceride as they relate to whole body energy expenditure and fuel preference during the development of obesity.